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Genetic Association Between Alzheimer's Disease Risk Variant Of ISSN 0006-2979, Biochemistry (Moscow), 2018, Vol. 83, No. 9, pp. 1075-1082. © Pleiades Publishing, Ltd., 2018. Original Russian Text © N. V. Ponomareva, T. V. Andreeva, M. A. Protasova, Yu. V. Filippova, E. P. Kolesnikova, V. F. Fokin, S. N. Illarioshkin, E. I. Rogaev, 2018, published in Biokhimiya, 2018, Vol. 83, No. 9, pp. 1351-1360. Genetic Association between Alzheimer’s Disease Risk Variant of the PICALM Gene and Auditory Event-Related Potentials in Aging N. V. Ponomareva1,2,a*, T. V. Andreeva2,3, M. A. Protasova2, Yu. V. Filippova1, E. P. Kolesnikova1, V. F. Fokin1, S. N. Illarioshkin1, and E. I. Rogaev2,3,4,b* 1Research Center for Neurology, 125367 Moscow, Russia 2Vavilov Institute of General Genetics, Russian Academy of Sciences, 119991 Moscow, Russia 3Lomonosov Moscow State University, Department of Biology, Center of Genetics and Genetic Technologies, 119991 Moscow, Russia 4Brudnick Neuropsychiatric Research Institute, Department of Psychiatry, University of Massachusetts Medical School, Worcester, USA ae-mail: [email protected] be-mail: [email protected] Received May 21, 2018 Revision received June 26, 2018 Abstract—Aging and genetic predisposition are major risk factors in age-related neurodegenerative disorders. The most common neurodegenerative disorder is Alzheimer’s disease (AD). Genome-wide association studies (GWAS) have identi- fied statistically significant association of the PICALM rs3851179 polymorphism with AD. The PICALM G allele increases the risk of AD, while the A allele has a protective effect. We examined the association of the PICALM rs3851179 polymor- phism with parameters of the P3 component of auditory event-related potentials (ERPs) in 87 non-demented volunteers (age, 19-77 years) subdivided into two cohorts younger and older than 50 years of age. We found statistically significant asso- ciation between the AD risk variant PICALM GG and increase in the P3 latency in subjects over 50 years old. The age- dependent increase in the P3 latency was more pronounced in the PICALM GG carriers than in the carriers of the PICALM AA and PICALM AG genotypes. The observed PICALM-associated changes in the neurophysiological processes indicate a decline in the information processing speed with aging due, probably, to neuronal dysfunction and subclinical neurodegen- eration of the neuronal networks in the hippocampus and the frontal and parietal cortical areas. Such changes were less pro- nounced in the carriers of the PICALM gene A allele, which might explain the protective effect of this allele in the cognitive decline and AD development. DOI: 10.1134/S0006297918090092 Keywords: PICALM genotype, neurodegeneration, aging, genetic predisposition, Alzheimer’s disease, event-related poten- tials, P300 Aging and genetic predisposition are the greatest Polymorphism of the apolipoprotein E gene (ApoE) known risk factors in the development of age-related neu- located on chromosome 19 is the most common AD risk rodegenerative disorders, the most common of which are factor. The ApoE ε4 allele markedly elevates the risk of Alzheimer’s disease (AD) and Parkinson’s disease (PD). AD; however, it is not necessary or sufficient for AD The development of AD, especially of the early- development [6, 7]. onset familial AD, is related to mutations in the genes Recently, a remarkable progress in identifying new encoding presenilin 1 (PSEN1) [1, 2], presenilin 2 genes with lower impact and penetrance but still associat- (PSEN2) [2-4], and amyloid precursor protein (APP) [5]. ed with increased risk of AD development, has been achieved by using genome-wide association studies Abbreviations: AD, Alzheimer’s disease; EEG, electroen- (GWAS). Thus, it was found that the PICALM rs3851179 cephalogram; ERPs, event-related potentials; LP, latency peri- polymorphism is associated with the AD development [8, od; PD, Parkinson’s disease. 9]. PICALM (chromosome 11q14) has been described as * To whom correspondence should be addressed. one of the six most common risk genes in the AlzGene 1075 1076 PONOMAREVA et al. susceptibility gene database (http://www.AlzGene.org). ly in AD [23, 26, 28, 30]. The amplitude of P3 decreases The PICALM allele G increases the risk of AD develop- in AD (the data on P3 amplitude in normal aging are con- ment, while the A allele decreases this risk [10, 11]. It was troversial) [28, 31]. found that epistatic and additive interaction between Several studies have demonstrated an association genes identified in GWAS (including PICALM and ApoE between the genetic risk factors for AD and the parame- genotypes) might be involved in AD development [12, 13]. ters of cognitive ERPs. Analysis of cognitive ERPs in a PICALM encodes phosphatidylinositol-binding small cohort of 30 elderly females including 10 carriers of clathrin assembly protein involved in clathrin-mediated the ApoE E4+ genotype found that the latency of the P3 endocytosis (CME) [14]. CME is a component of some component of auditory ERPs in the examined subjects metabolic pathways playing a crucial role in AD patho- increased, while the neuropsychological parameters of genesis, such as formation and clearance of β-amyloid memory were comparable between ApoE E4+ carriers and and tau protein clearance by autophagy [15-17]. non-carriers [32]. It was also shown that the P3 latency PICALM modulates neuronal trafficking, including the was increased in clinically asymptomatic relatives of AD transport of synaptic vesicle protein VAMP2 required for patients [33]. Similarly, elevated latency of the late com- the neurotransmitter release from presynaptic terminals ponents of visual ERPs was found in clinically asympto- [18]. It was found that PICALM expression depends on matic relatives of AD patients [34]. the PICALM rs3851179 polymorphism [19]. The impact of PICALM polymorphism on cognitive The PICALM rs3851179 polymorphism is associated ERPs in normal aging and neurodegenerative diseases with the hippocampus size and the entorhinal cortex remains unexplored. thickness in healthy individuals, patients with mild cogni- Our study was aimed at investigating the association tive impairment (MCI), and AD patients [20, 21]. between the PICALM rs3851179 polymorphism and the Earlier, we investigated the functional role of the P3 component of auditory ERPs and how it might be PICALM rs3851179 polymorphism using the resting-state affected by aging. quantitative electroencephalography (qEEG) and revealed association between the studied PICALM polymorphism and age-related changes in the β EEG activity [22]. MATERIALS AND METHODS Other sensitive tools that can be used for assessing functional changes in the brain in normal and pathologi- Subjects. A total of 87 non-demented volunteers, 43 cal aging are cognitive components of event-related males and 44 females, aged 19-77 (mean age, 48.0 ± 1.7 potentials (ERPs) that reflect brain activity directly years) were examined after undergoing neurological and involved in decision making, memory, and attention. psychometric examination. The exclusion criteria were as ERPs generation is a result of summation of excitatory follows: neurological or mental disorders including cardio- and inhibitory postsynaptic potentials (EPSPs and IPSPs, vascular diseases, psychiatric diseases, epilepsy, as well as respectively) mainly in the pyramidal neurons of the psychiatric or neurological disorders in subject’s history. frontal, parietal, and temporal cortical structures and the All subjects were divided into groups according to the hippocampus [23-27]. Cognitive ERPs have been used to PICALM rs3851179 polymorphism. The PICALM AA&AG examine neurophysiological mechanisms underlying cog- group consisted of homozygous PICALM AA or heterozy- nitive disorders in aging and neurodegenerative diseases gous PICALM AG carriers; the PICALM GG group includ- (e.g., MCI, AD, and PD) [26, 28, 29]. This method sur- ed homozygous PICALM GG carriers. Each group was fur- passes functional magnetic resonance imaging in tempo- ther subdivided into subgroups with subjects younger and ral resolution (but not in spatial resolution). older than 50 years of age. The most studied and informative parameter is the All subjects were genotyped for ApoE. ERPs positive P3 component (P300) elicited ~300 ms Cognitive auditory ERPs recordings. Cognitive audi- after the onset of a rare stimulus in the cognitive task tory ERPs were recorded with a computerized Neuro- involving identification of rare “target” stimuli within a KM system (Statokin, Russia) using the monopolar series of frequently presented “standard” stimuli (the so- recording in the parietal (P3, P4), frontal (F3, F4) and called oddball paradigm). central (Cz) areas according to the International 10-20 Multiple studies (including intracranial ones) System. Auditory ERPs were recorded according to a demonstrated that the P3 component is mainly elicited by standard auditory discrimination protocol using target the neuronal networks of the frontal, temporal, and pari- and non-target stimuli (oddball paradigm). The target etal cortical areas and the hippocampus, the frontal cortex stimuli were recognized as 2000-Hz clicks among fre- being responsible predominantly for attention, while tem- quent 1000-Hz standard stimuli. The subject was required poral and parietal areas – for memory functions [26, 27]. to distinguish between the two tones by mentally counting The P3 latency gradually increases with normal the target tones and not responding to the standard. aging, and it is significantly elevated in neurodegenerative
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